Major Depressive Disorder (MDD) is the most potent psychiatric risk factor for suicidal behavior in adolescents, yet most depressed youth never attempt suicide, diminishing the positive predictive value of a diagnosis of MDD in gauging the risk of future suicidal acts. Efforts to prevent youth suicide would benefit greatly from a deeper understanding of precursors and pathways to suicidal behavior in depressed youth, particularly if such knowledge informs the development of effective risk evaluation and intervention strategies. Knowledge of measurable factors that increase the risk of future suicide attempts in depressed adolescents could prove critical to efforts to prevent youth suicide by virtue of: 1) aiding in the recognition of depressed youth at especially heightened risk for suicide, who at a minimum may require closer supervision and containment;2) identifying targets for clinical intervention beyond the mood disorder per se;and, 3) contributing to the development of assessment tools and risk markers relevant to better gauging individual suicide risk and informing clinical intervention research with youth at risk for suicide. The proposed R01 application from an early stage investigator (ESI) will address critical gaps in knowledge by examining the role of impulsive aggression and neurocognitive functioning in the etiopathogenesis of suicidal behavior in adolescents with MDD. The central hypothesis is that impulsive aggression and deficits in executive function and decision making will contribute substantially to a model of future suicide attempts and add positive predictive value to traditional assessment approaches. Our hypothesis is informed by promising pilot work in which measures of impulsive aggression and decision making deficits sharply distinguished depressed adolescent suicide attempters from non-attempters. The design includes cross-sectional comparisons as well as a prospective longitudinal study of 300 depressed youth with and without a prior history of suicide attempt, followed from early to middle adolescence, the developmental period of highest risk for suicidal behavior. These results will contribute to the mission of the NIMH by improving our capacity to identify the temporal and likely causal sequence of antecedents to future suicidal acts in youth with MDD, thus framing targets for practical clinical risk assessment, intervention, and the prevention of suicidal behavior. PUBLIC HEALTH RELEVANCE: The severe consequences of adolescent suicidal behavior make the accurate identification of youth at high risk an important clinical, research, and public health objective. This is the first large-scale prospective study of the developmental antecedents of adolescent suicidal behavior to comprehensively address multiple risk and protective factors in depressed youth. With the use of a multi-method, state-of-the-art, and pilot tested approach for assessing impulsive aggression and an informative computerized battery of subtests of executive function and decision making, the proposed research may help to clarify the specific behavioral and neurocognitive pathways contributing to the etiopathogenesis of suicidal behavior. Thus, this work has the potential to inform the development of practical suicide risk evaluation tools, empirically-based treatments, and preventive interventions to reduce adolescent suicide.